Although individuals with severe persistent asthma constitute the minority of patients with asthma in terms of prevalence, they represent the group with the highest morbidity both individually and for society in general. Indeed, they have the greatest impairment in terms of quality of life. Their disease has profound impact on the health care system, and their treatment uses a disproportionate amount of health care dollars. Moreover, ethnic minorities and women disproportionately share this burden. Although the currently funded Asthma Clinical Research Network (ACRN) has contributed substantially to a more comprehensive understanding of asthma pathogenesis and treatment, all of the protocols performed thus far have focused on patients with mild to moderate asthma. This lack of previous ACRN protocol development in severe persistent asthma, the increasing recognition of the importance of this group of patients in terms of morbidity and mortality within the international scientific community, and the ongoing work being conducted by various NHLBI-funded centers to characterize this group of patients make protocols focused on the treatment of severe persistent asthma a logical and important next step for the newly created ACRN funded by this RFA. To address this need, we have developed two protocols that deal with Severe Persistent Asthma (SPA), termed SPA-1 and SPA-2. To maximize subject eligibility and enrollment, a unique feature of SPA-1 and SPA-2 is that they share a common initial period, termed the Asthma Characterization Phase (ACP). During the ACP, aggravating conditions, corticosteroid requirements, and overall asthma stability will be assessed and managed following standardization of therapy on an inhaled corticosteroid (ICS) in combination with a long acting beta agonist prior to allocation into one of the two protocols. SPA-1 will enroll subjects who have unstable disease despite receiving high doses of ICS and randomize them into a double-blind cross-over trial that will evaluate the efficacy of adding either theophylline or a leukotdene receptor antagonist, two approaches recommended by treatment guidelines but not proven to be effective in this group of patients. SPA-2 will enroll subjects who are unable to wean successfully from oral corticosteroids and randomize them into a double-blind cross-over trial that will evaluate the efficacy of targeting either chronic infection (macrolide antibiotic) or refractory inflammation (immunosuppressive therapy with mycophenolate mefetil) as a means of first, improving symptom control (Phase 1), and second, reducing oral corticosteroid burden (Phase 2). As companion studies, SPA-1 and SPA-2 are uniquely designed to maximize subject enrollment that will provide essential evidence-based recommendations for the effective and safe treatment of various phenotypic patterns of patients with severe persistent asthma.